Project Summary Endometriosis is one of the few disorders in women's health research with little progress made in the last 20 years relative to screening, detection, prognosis, and treatment. Reactive aldehydes, formed during oxidative stress, are produced and elevated in women with endometriosis and are metabolized intracellularly by aldehyde dehydrogenase 2 (ALDH2). The central hypothesis of this K99/R00 proposal is that the balance of reactive aldehyde production and metabolism underlies endometriosis and endometriosis-associated pain. The research goal of this project is to determine the role of reactive aldehyde production and aldehyde metabolism in endometriosis to identify a novel treatment and biomarker for women suffering from endometriosis. This proposal includes a comprehensive research training and career development plan under the guidance of expert mentors, advisors, and contributors (Drs. Eric Gross, Daria Mochly-Rosen, Marcia Stefanick, Julie Christianson, and Linda Giudice). The Mentored Phase will be conducted at Stanford University School of Medicine, a world-class environment for training in cutting edge research and career development. During the K99 mentored training phase (Years 1-2): Aim 1 will determine if reactive aldehyde metabolism influences the development of endometriosis using ALDH2*2 knock-in mice with reduced aldehyde metabolism, an experimental model of endometriosis, and cutting-edge techniques to measure reactive aldehyde production and aldehyde metabolism. Aim 2 will determine if reactive aldehyde metabolism is altered in women with endometriosis using techniques from Aim 1 to analyze human endometrial tissue samples from women with and without endometriosis provided by the UCSF endometrial tissue bank. This phase will consist of training in biochemical techniques to measure reactive aldehyde production and metabolism, formal course work, mentoring, grant writing, and seminars to prepare Dr. Stacy McAllister for a career as an independent investigator in the women's health field with a particular focus on endometriosis. During the R00 independent research phase (Years 3-5): Aim 3 will determine if reactive aldehyde metabolism influences endometriosis-associated primary abdominal and secondary vaginal pain (hyperalgesia) using the skills mastered in the training phase, an endometriosis experimental model, unique equipment and specialized skills to assess hyperalgesia, and a novel ALDH2 activator (to increase reactive aldehyde metabolism). Overall, this research proposal addresses an important issue outlined by the NICHD mission statement that women suffer no harmful effects from the reproductive process. Further, this proposal will train a future leader in the endometriosis field to tackle the major health problem facing 1 in 10 women of childbearing age.